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  3. Repurposing nitric oxide donating drugs in cancer therapy through immune modulation

Repurposing nitric oxide donating drugs in cancer therapy through immune modulation

  • J Exp Clin Cancer Res. 2023 Jan 14;42(1):22. doi: 10.1186/s13046-022-02590-0.
Chung-Yen Li 1,  Gangga Anuraga 2 3,  Chih-Peng Chang 1 4,  Tzu-Yang Weng 1,  Hui-Ping Hsu 5,  Hoang Dang Khoa Ta 2,  Pei-Fang Su 6,  Pin-Hsuan Chiu 7,  Shiang-Jie Yang 1,  Feng-Wei Chen 1,  Pei-Hsuan Ye 8,  Chih-Yang Wang 9 10 11,  Ming-Derg Lai 12 13
Affiliations

Affiliations

  • 1 College of Medicine, Institute of basic medical sciences, National Cheng Kung University, Tainan, Taiwan, ROC.
  • 2 PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan, ROC.
  • 3 Department of Statistics, Faculty of Science and Technology, Universitas PGRI Adi Buana, Surabaya, Indonesia.
  • 4 Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
  • 5 Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
  • 6 Department of Statistics, National Cheng Kung University, Tainan, Taiwan, ROC.
  • 7 The Center for Quantitative Sciences, Clinical Medicine Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
  • 8 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
  • 9 PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan, ROC. chihyang@tmu.edu.tw.
  • 10 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. chihyang@tmu.edu.tw.
  • 11 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. chihyang@tmu.edu.tw.
  • 12 College of Medicine, Institute of basic medical sciences, National Cheng Kung University, Tainan, Taiwan, ROC. a1211207@mail.ncku.edu.tw.
  • 13 Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC. a1211207@mail.ncku.edu.tw.
PMID: 36639681 DOI: 10.1186/s13046-022-02590-0
Abstract

Background: Nitric oxide-releasing drugs are used for cardiovascular diseases; however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice.

Methods: The effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon Cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA Sequencing.

Results: Low doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NOD/SCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8+ T cells with activation gene signatures, as indicated by single-cell RNA Sequencing. Flow cytometry analysis confirmed an increase in infiltrating CD8+ T cells and dendritic cells. The antitumor effect of nitric oxide donors was abolished by depletion of CD8+ T cells, indicating the requirement for CD8+ T cells. Tumor inhibition correlated with a decrease in a subtype of protumor macrophages and an increase in a subset of Arg1-positive macrophages expressing antitumor gene signatures. The increase in this subset of macrophages was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin induced an additive Cancer therapeutic effect in two immunocompetent animal models. The enhanced therapeutic effect was accompanied by an increase in the cells expressing the gene signature of NK cell.

Conclusions: Low concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8+ T cells are essential for antitumor effects. In addition, low-dose nitric oxide donors may be combined with chemotherapeutic drugs in Cancer therapy in the future.

Keywords

CD8+ cytotoxic T cells; Cancer; Immune; Macrophages; Nitric oxide donor; SNAP; Single-cell RNA-seq.

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